Pharmaceutical foams are pressurized dosage forms containing one or more active ingredients that, upon valve actuation, emit a fine dispersion of liquid and/or solid materials in a gaseous medium. Foam formulations are generally easier to apply, are less dense, and spread more easily than other topical dosage forms. Foams may be formulated in various ways to provide emollient or drying functions to the skin, depending on the formulation constituents. Accordingly, this delivery technology is a useful addition to the spectrum of formulations available for topical use. However, as yet, only a few pharmaceutical foams are commercially available. Most commercially available foam dosage forms contain corticosteroids, although some products have also been used to deliver antiseptics, antifungal agents, anti-inflammatory agents, local anesthetic agents, skin emollients, and protectants (American Journal of Drug Delivery, 2003, vol. 1(1), pp. 71-75).
There is growing interest in converting non-foam topical treatments to aerosol foam or mousse formulations, which better penetrate the skin, provide faster treatment and do not leave any greasy residue on skin or clothing compared with conventional ointments. Until now, the most common gas propellant used in aerosol products is chlorofluorocarbon (CFC), an ozone-depleting agent. The Montreal Protocol International Treaty, signed by 180 nations, banned the use of chlorofluorocarbons (CFCs) as aerosol propellants and mandated the phasing out of CFC agents. No new or revised aerosol formulations may contain CFC propellants and alternative propellants must be used that are more environmentally friendly. Therefore, manufacturers must reformulate or modify existing products to use non-CFC propellants, while maintaining important aspects of the previous formulation, such as accuracy of delivery, stability, etc. The primary CFC substitute are hydrofluoroalkanes (HFA), also known as hydrofluorocarbons (HFC).
Although hydrocarbon propellants, such as propane and butane, can be used in the manufacturing of pharmaceutical foams, these propellants are not suited for human use since they are flammable. Just as is the case with CFC propellants, hydrofluoroalkanes (HFAs) that possess high chemical stability can be used as a primary substitute for hydrocarbons. Examples of HFAs are 1,1,1,2,3,3,3-heptafluoropropane (HFA-134a) and 1,1,1,2-tetrafluoroethane (HFA-227). Hydrofluoroalkanes (HFAs) are also referred to as hydrofluorocarbons (HFCs) and these terms are used interchangeably.
Since replacing a component of any formulation means introducing new properties, and HFAs differ in their solvating power from CFCs and hydrocarbons, providing reproducible performance of reformulated aerosols for pharmaceutical uses represents a challenging task. Co-solvents (such as ethanol) are often incorporated into the formulation in order to arrive at a stable product (Pharmaceutical Aerosols, June 2003, p. 21). Such formulations, however, have a number of undesirable aspects. Alcohol co-solvents can dry and irritate the skin. U.S. Pat. No. 6,126,920 suggests that the use of alcohol co-solvents can lead to burning, itching, and irritation observed in the use of topical foam for delivering betamethasone. Further, volatile alcohols are highly irritating to mucous membranes.
Formulations that contain volatile alcohols and/or alkanes are potential safety hazards due to the high flammability of the product. Moreover, the flammability characteristics of the product require expensive precautions during manufacturing, and may require controlled environments for storage and for disposal of containers after use. For example, WO 85/01876 describes the fire hazards associated with alcohol- and alkane-containing aerosol foam formulations.
Pharmaceutical foam formulations containing keratolytic agents have not been described in the literature. Keratolytic agents are agents that soften, separate, and cause desquamation (i.e. shedding or peeling) of the cornified epithelium, or horny layer, of the skin. These agents are used to expose mycelia of infecting fungi or to treat corns, warts, and certain other skin diseases. Commonly used keratolytic agents include urea, urea in combination with ammonium lactate, salicylic acid, papain, papain in combination with urea, and sulfur. Sulfur is also used in combination with sodium sulfacetamide to treat acne, rosacea, seborrheic dermatitis, eczema, xerosis, scabies, pediculosis and psoriasis.
Keratolyic agents can be administered in the form of a liquid, cream, lotion or cleanser. Topical formulations containing keratolytic agents typically have an intense color and/or strong odor. For example, sulfur containing products typically have an intense yellow color and/or a strong odor characteristic of sulfur. Urea-containing products frequently exhibit a strong ammonia odor, while papain-containing products exhibit a distinctive papain odor. Current products on the market typically contain substantial amounts of odor masking agents, such as fragrances, in order to mask or shield the odor associated with the pharmaceutical agent. However, the use of high concentrations of fragrances can be problematic. The use of fragrances in topical formulations can result in skin sensitizing reactions in which the patient develops sensitivity to the odor masking agent. Furthermore, the presence of fragrances, which are often complex mixtures of different compounds, may result in undesirable side reactions between the fragrance and the active agent(s).
There exists a need for topical keratolytic foam formulations which, once applied to the skin, have little or no odor or color and are non-staining and which contain little or no odor masking agents such as fragrances.
It is therefore an object of the invention to provide alcohol-free keratolytic topical foam aerosol formulations that use hydrofluoroalkanes (HFAs) as the propellant.
It is a further object of the invention to provide keratolytic topical foam formulations which exhibit reduced intensity of the odor and/or color associated with the keratolytic agent.